Advances in Sickle Cell Disease

St. Jude researchers have played integral roles in advancing our understanding of SCD, and therapies born from basic research have been successfully translated into clinical therapies for children with SCD. In fact, the first research grant St. Jude received was dedicated to studying SCD and to this day, St. Jude continues its dedication to SCD treatments and cures. The institution has one of the largest SCD treatment programs in the country, caring for almost 1,000 children with SCD and even offering assistance with transition care.

Leveraging their understanding of the science behind the blood disorder, St. Jude researchers surmised that the effects of SCD could be ameliorated by modulating the amount of fetal hemoglobin present in red blood cells. Some of the most recent advances in the treatment of SCD have centered on this concept.

St. Jude researchers played a pivotal role in identifying hydroxyurea as a safe and effective treatment for sickle cell anemia in very young children. Hydroxyurea augments fetal hemoglobin levels and inhibits the polymerization of sickled adult hemoglobin. St. Jude-led studies showed that this drug lessened acute pain, lowered the number of blood transfusions and hospitalization rates for infants and toddlers. Research pertaining to hydroxyurea, including novel ways to increase adherence, is ongoing as it continues to be a first line of treatment for many with SCD.  

Modulating fetal hemoglobin requires an understanding of the basic science driving γ-globin gene expression. Researchers have made important discoveries that tease apart the regulation of fetal hemoglobin. Two activator sequences and repressor sequences were identified, which aid in modulating the γ-to-β-globin gene switch, and researchers have also discovered that hypoxia inducible factor 1 (HIF1) promotes expression of γ-globin under low-oxygen conditions. Studies like these provide a clearer understanding of the regulation of fetal hemoglobin and open the door for the development of new therapeutic targets.

Experiments aimed at understanding the regulatory circuitry controlling fetal hemoglobin expression are ongoing and will most certainly lay the foundation for the next generation of clinical treatments.

In the 1980s, a St. Jude patient was undergoing a bone marrow transplant for leukemia. This treatment also eliminated her sickle cell anemia. The case study, published in the New England Journal of Medicine, proved that bone marrow transplantations could cure SCD.

While transplantation has approximately an 85% success rate (if the donor is a relative and human leukocyte antigen-matched), this approach is limited to a select few patients—less than 20%—due to the potential for complications, thus underscoring the need for alternative treatment options.

With the advent of genome editing, St. Jude researchers have developed and optimized gene editing strategies for SCD. Researchers have set their sights on applying genome editing to induce fetal hemoglobin in patients.

St. Jude established the St. Jude Collaborative Research Consortium for Sickle Cell Disease (CRC-SCD) aimed at teasing apart the molecular mechanisms enabling the γ-to-β-globin gene switch and how to precisely control this switch. The CRC-SCD has focused on how to utilize gene therapy strategies such as CRISPR-Cas9, base editing and prime editing to treat SCD.
 

CRISPR-Cas9 genome editing of hematopoietic stem cells was one of the first genome editing strategies employed for SCD. St. Jude researchers showed that CRISPR-Cas9 technology could successfully mutate a short nucleotide sequence in the promoters of HBG1 and HBG2, leading to an increase in fetal hemoglobin. This finding identified attractive DNA targets for SCD and other β-hemoglobinopathies and has subsequently shown to be effective in clinical studies.

St. Jude scientists are also on the cutting edge of adapting novel genome strategies to treat SCD. Base editors combine CRISPR-Cas9 technology with a nucleoside deaminase, resulting in specific transition and transversion mutations in a desired target region. Base editors have shown great promise in preclinical studies and have recently been used to create a TAL1 transcription factor binding site to induce fetal hemoglobin. The results showed this approach was more precise than CRISPR-Cas9, consistently raised fetal hemoglobin levels and should continue to be tested in a translational capacity.

Furthermore, researchers have demonstrated that a newer type of genome editing, called prime editing, can efficiently replace disease-causing mutations in the adult hemoglobin gene with a healthy gene sequence. Prime editing can facilitate insertions, deletions and 12 types of point mutations. Results of a 2023 publication showed that a prime-edited correction converted up to 41% of blood stem cells from SCD patients. Considering that prior work has shown that conversion rates over 20% are likely to be therapeutically relevant, this approach stands to greatly inform the next generation of SCD treatments. 

Researchers are focused on the development of newer, more sensitive and efficient ways to utilize genome editing technology and minimize off-target effects. Dedicated basic and translational research programs here at St. Jude will allow treatment strategies to move from simply managing symptoms to a more preventative approach, thereby circumventing multisystem organ damage that so often occurs in those with SCD.